The use of amino acid surrogates is proposed as an intermediate structure activity probe for polypeptides between isotopic substitution and amino acid substitution. These surrogates are for the most part non-naturally occurring alpha-amino acids which have steric parameters closely similar to the authentic residues, but differ slightly in their electronic structural characteristics. The synthesis of several such surrogates is outlined, including thioasparagine, thioglutamine, and a thiazolyl alanine. These will be incorporated into hormonal polypeptides sych as oxytocin and vasopressin in place of asparagine, glutamine, and phenylalanine, and biological activities will be determined by standard assay methods. In addition, feasibility studies will be conducted on the synthesis of a 4-hydroxy thiazole derivative as a potnetial tyrosine surrogate. The incorporation of these analogs within other polypeptide hormones such as the releasing and release-inhibiting factors of the hypothalamus will also be pursued. Both solution and solid phase methods of peptide synthesis will be utilized as appropriate. Such studies should indicate much more clearly which structural features (as opposed to conformational parameters) are responsible for intrinsic activity and/or binding of these hormones. This knowledge may then lead to the design of structures incorporating these surrogates which will behave as hormonal antagonists. Such compounds are of tremendous interest in view of their potential significance to population, economic, and health-related problems.